Our long-term objective is to reintroduce voluntary control to denervated skeletal muscles by establishing functional connections between damaged spinal circuitry, transplanted neurons, and muscles, a major issue for rehabilitation in neurodegenerative diseases and after trauma. Embryonic ventral spinal cord cells will be transplanted into peripheral nerve of adult Fischer rats as a replacement neuron source to reinnervate muscles that have been denervated completely by spinal cord injury (SCI) or peripheral nerve section.
Our Specific aims are: 1) to assess whether motoneuron survival and muscle reinnervation change with cotransplantation of embryonic neurons and Schwann cells transduced to produce neurotrophic and/or angiogenic factors; 2) to evaluate whether acute or chronic depolarization of the transplant or muscle by electrical stimulation influences motoneuron survival, muscle reinnervation, atrophy and strength; 3) to determine whether a peripheral nerve graft that houses embryonic neurons can be a bridge to connect contused lumbar spinal cord to denervated hind limb muscles. Four, 10 or 20 weeks after cell transplantation, assessments of neuron (motoneuron) numbers, myelinated axons, neuromuscular junctions, reinnervated muscle fibers, muscle fiber area, reinnervated motor units, muscle strength and fatigue will be made. Hind limb function will be assessed by behavioral tests each week. The source of axon growth will be determined by retrograde tracing. Re- establishment of neuromuscular junctions will reduce muscle atrophy, increase muscle excitability and permit restoration of limb movements by patterned electrical stimulation. Uniting neuron transplants with the spinal cord is a potential way for central structures to communicate with muscles again. If muscle reinnervation is widespread, use of neuron transplants in peripheral nerve could restore control of muscle in neurodegenerative diseases like amyotrophic lateral sclerosis and after trauma such as spinal cord injury.
Death of motoneurons after trauma such as spinal cord injury and in neurodegenerative diseases like amyotrophic lateral sclerosis induces widespread denervation of muscles. Examining the ability of embryonic neurons to survive in peripheral nerve and to form functional connections both with the injured central nervous system and with muscle will show the potential of these neurons to restore muscle control.
|Liu, Yang; Grumbles, Robert M; Thomas, Christine K (2014) Electrical stimulation of transplanted motoneurons improves motor unit formation. J Neurophysiol 112:660-70|
|Grumbles, Robert M; Liu, Yang; Thomas, Christie M et al. (2013) Acute stimulation of transplanted neurons improves motoneuron survival, axon growth, and muscle reinnervation. J Neurotrauma 30:1062-9|
|Liu, Yang; Grumbles, Robert M; Thomas, Christine K (2013) Electrical stimulation of embryonic neurons for 1 hour improves axon regeneration and the number of reinnervated muscles that function. J Neuropathol Exp Neurol 72:697-707|
|Grumbles, Robert M; Almeida, Vania W; Casella, Gizelda T B et al. (2012) Motoneuron replacement for reinnervation of skeletal muscle in adult rats. J Neuropathol Exp Neurol 71:921-30|
|Casella, Gizelda T B; Almeida, Vania W; Grumbles, Robert M et al. (2010) Neurotrophic factors improve muscle reinnervation from embryonic neurons. Muscle Nerve 42:788-97|
|Grumbles, Robert M; Sesodia, Sanjay; Wood, Patrick M et al. (2009) Neurotrophic factors improve motoneuron survival and function of muscle reinnervated by embryonic neurons. J Neuropathol Exp Neurol 68:736-46|